What GLP-1 (Glucagon-like peptide-1) receptor agonists have proven benefits for patients with Chronic Kidney Disease (CKD)?

GLP-1 Receptor Agonists with Proven CKD Benefit

Liraglutide, semaglutide, and dulaglutide are the GLP-1 receptor agonists with proven cardiovascular and kidney benefits that should be prioritized for patients with type 2 diabetes and CKD. 1

Preferred Agents with Evidence

The following GLP-1 RAs have demonstrated both cardiovascular and kidney benefits in large outcome trials:

• Liraglutide: Demonstrated greater MACE reduction in patients with eGFR <60 ml/min/1.73 m² compared to those with higher eGFR 1
• Semaglutide (injectable): Can be used without dose adjustment across all levels of kidney function, including ESRD and dialysis 2; reduced primary kidney endpoint by 24% in the FLOW trial 3, 4
• Dulaglutide: Produced significantly slower GFR decline compared to insulin glargine in patients with moderate-to-severe CKD (stages G3 and G4) 1; can be used without dose adjustment in patients with eGFR >15 ml/min/1.73 m² 2

Note: Albiglutide also showed cardiovascular and CKD benefits but is not currently available. 1

Agents to AVOID in Advanced CKD

• Exenatide: Contraindicated in severe renal impairment and ESRD due to renal elimination 2
• Lixisenatide: Contraindicated in severe renal impairment and ESRD 2

Kidney-Specific Benefits Demonstrated

GLP-1 RAs with favorable outcomes reduced risk for composite kidney disease outcomes including:

• Macroalbuminuria (primary driver of benefit) 1
• eGFR decline 1
• Progression to kidney failure 1
• Death from kidney disease 1

Clinical Algorithm for Use

Step 1: Determine eGFR and current medications

• If eGFR ≥30 ml/min/1.73 m²: Start with metformin and/or SGLT2i as first-line 1
• If eGFR <30 ml/min/1.73 m²: Metformin contraindicated; SGLT2i has minimal glycemic effect 1, 2

Step 2: Add GLP-1 RA if glycemic targets not met

• Choose liraglutide, semaglutide, or dulaglutide 1
• These agents retain glucose-lowering potency across the full range of eGFR, including dialysis patients 1, 2

Step 3: Adjust concomitant medications

• Reduce insulin dose by approximately 20% when initiating GLP-1 RA to prevent hypoglycemia 2
• Reduce sulfonylurea doses to avoid hypoglycemia 1
• Do NOT combine with DPP-4 inhibitors 2

Step 4: Titrate slowly and monitor

• Start low and titrate gradually to minimize gastrointestinal side effects (nausea, vomiting, diarrhea occur in 15-20% of patients with CKD stages G3-G4) 1
• Monitor kidney function every 3-6 months 2
• Watch for severe GI symptoms that could lead to dehydration and acute kidney injury 2, 5

Critical Pitfalls to Avoid

• Do NOT use exenatide or lixisenatide in ESRD - these are absolute contraindications 2
• Do NOT forget to reduce insulin/sulfonylurea doses when starting GLP-1 RA to prevent hypoglycemia 2
• Do NOT ignore severe nausea/vomiting - can cause dehydration and AKI in vulnerable CKD patients 2, 5
• Do NOT use in malnourished patients - weight loss may be detrimental 2
• Do NOT use in patients with personal/family history of medullary thyroid carcinoma or MEN2 - FDA Black Box Warning 5

Special Considerations

• For obese CKD patients exceeding BMI limits for kidney transplant listing, GLP-1 RAs can facilitate weight loss to meet eligibility criteria 2
• GLP-1 RAs do not cause hypoglycemia when used alone 2
• Heart rate typically increases by ~5 bpm but has not been associated with adverse cardiovascular events 1
• Semaglutide is available in oral formulation for patients who prefer non-injectable options 1